The world’s first successful transplantation of a genetically altered pig heart into a human patient was documented in a recent study that was just published in The Lancet. This analysis is the most thorough to date. Physician-scientists from the University of Maryland School of Medicine (UMSOM) performed this ground-breaking treatment in January 2022, a significant turning point for medical research.
The University of Maryland Medical Centre provided care for the patient, 57-year-old David Bennett, Sr. For almost seven weeks following surgery, he had robust heart function and no visible symptoms of acute rejection. He passed away two months after receiving a transplant due to an unexpected development of heart failure.
Since then, the transplant group has conducted in-depth research into the physiological mechanisms that resulted in heart failure to pinpoint potential issues that could be avoided in subsequent transplants to increase the likelihood of longer-term success.
Muhammad M. Mohiuddin, MD, Professor of Surgery and Scientific/Program Director of the Cardiac Xenotransplantation Programme at UMSOM remarked, “Our paper provides important insight into how a multitude of factors likely played a role in the functional decline of the transplanted heart.” “As we gear up for clinical studies of xenotransplants using pig organs, we aim to keep moving this field forward.”
Mr. Bennett, who was dying from end-stage cardiac failure, was not a candidate for a conventional heart transplant. Under its extended access (compassionate use) provision, the U.S. Food and Drug Administration approved the procedure.
“We were driven to put a light on what’s led to the heart transplant’s dysfunction in Mr. Bennett, who performed a heroic act by volunteering to be the first in the world,” said Bartley Griffith, MD, an assistant professor of surgery and The Thomas E. and Alice Marie Hales Distinguished Professor in Transplantation at UMSOM and a co-author of the study. With a xenotransplant, we want our next patient to not only live longer but also adjust to normal life again and flourish for months or even years.
The research team extensively tested the patient’s scanty tissues to comprehend the mechanisms that resulted in the pig heart transplant’s malfunction. They meticulously charted the events that eventually resulted in heart failure, showing that the heart was healthy and generally functioning until day 47 following surgery on imaging tests like an echocardiogram.
The latest study reveals no symptoms of acute rejection in the initial weeks following the transplant. Mr. Bennett’s heart failure was likely caused by several interrelated events, including his poor health before the transplant, which left him highly immunocompromised. This restricted the application of an efficient anti-rejection regimen utilized in xenotransplantation preclinical research. The researchers discovered that the patient was likely more susceptible due to organ rejection brought on by immune system-produced antibodies.
The researchers discovered inferential evidence of antibody-mediated rejection based on histology, immunohistochemical labeling, and single-cell RNA analysis. Intravenous immunoglobulin, or IVIG, an antibody-containing medication, may also have facilitated cardiac muscle cell deterioration. It was administered to the patient twice during the second month following the transplant to avoid infection, and it most likely also elicited an anti-pig immunological reaction. The investigation team discovered proof that IgG antibodies were directed at the heart’s porcine vascular endothelium layer.
The current study also examined whether latent porcine cytomegalovirus (PCMV) was present in the pig heart, which may have affected the transplant’s failure. The virus may have been activated after the patient’s antiviral treatment program was scaled back to address other medical problems. This might have sparked an inflammatory reaction that harms cells. The virus did not infect the patient or spread to any organs besides the heart. For sensitive detection and exclusion of latent viruses for upcoming xenotransplants, improved PCMV testing techniques have been devised.
Mark T. Gladwin, MD, Vice President for Medical Affairs, University of Maryland, Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor, said valuable lessons could be drawn from this ground-breaking procedure and the brave first patient, Mr. Bennett. In the days, weeks, and months following the xenotransplant, our surgeon-scientists will use newly developed immune cell assays to track the patient. The promise of a life-saving invention will allow for stricter control of the first indications of rejection.